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J Med Chem. 2017 Dec 28;60(24):9976-9989. doi: 10.1021/acs.jmedchem.7b01192. Epub 2017 Oct 9.

Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii.

Author information

1
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco , San Francisco, California 94158, United States.
2
Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri 63130, United States.
3
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , St. Louis, Missouri 63130, United States.
4
Structural Genomics Consortium, University of Toronto , MaRS South Tower, 101 College St, Toronto, ON M5G 1L7, Canada.
5
Toronto General Hospital Research Institute , 200 Elizabeth St., Toronto, ON M5G 2C4, Canada.

Abstract

Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.

PMID:
28933846
PMCID:
PMC5746462
[Available on 2018-12-28]
DOI:
10.1021/acs.jmedchem.7b01192

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